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Molecular Cancer
Published in: Molecular Cancer 1/2014

Open Access 01-12-2014 | Research

Small molecule kinase inhibitor LRRK2-IN-1 demonstrates potent activity against colorectal and pancreatic cancer through inhibition of doublecortin-like kinase 1

Authors: Nathaniel Weygant, Dongfeng Qu, William L Berry, Randal May, Parthasarathy Chandrakesan, Daniel B Owen, Sripathi M Sureban, Naushad Ali, Ralf Janknecht, Courtney W Houchen

Published in: Molecular Cancer | Issue 1/2014

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Abstract

Background

Doublecortin-like kinase 1 (DCLK1) is emerging as a tumor specific stem cell marker in colorectal and pancreatic cancer. Previous in vitro and in vivo studies have demonstrated the therapeutic effects of inhibiting DCLK1 with small interfering RNA (siRNA) as well as genetically targeting the DCLK1+ cell for deletion. However, the effects of inhibiting DCLK1 kinase activity have not been studied directly. Therefore, we assessed the effects of inhibiting DCLK1 kinase activity using the novel small molecule kinase inhibitor, LRRK2-IN-1, which demonstrates significant affinity for DCLK1.

Results

Here we report that LRRK2-IN-1 demonstrates potent anti-cancer activity including inhibition of cancer cell proliferation, migration, and invasion as well as induction of apoptosis and cell cycle arrest. Additionally we found that it regulates stemness, epithelial-mesenchymal transition, and oncogenic targets on the molecular level. Moreover, we show that LRRK2-IN-1 suppresses DCLK1 kinase activity and downstream DCLK1 effector c-MYC, and demonstrate that DCLK1 kinase activity is a significant factor in resistance to LRRK2-IN-1.

Conclusions

Given DCLK1’s tumor stem cell marker status, a strong understanding of its biological role and interactions in gastrointestinal tumors may lead to discoveries that improve patient outcomes. The results of this study suggest that small molecule inhibitors of DCLK1 kinase should be further investigated as they may hold promise as anti-tumor stem cell drugs.
Appendix
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Metadata
Title
Small molecule kinase inhibitor LRRK2-IN-1 demonstrates potent activity against colorectal and pancreatic cancer through inhibition of doublecortin-like kinase 1
Authors
Nathaniel Weygant
Dongfeng Qu
William L Berry
Randal May
Parthasarathy Chandrakesan
Daniel B Owen
Sripathi M Sureban
Naushad Ali
Ralf Janknecht
Courtney W Houchen
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2014
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-13-103

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